Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of rat liver response to CYP450 inducers for array validation

ABSTRACT: The main objectives were to validate the DNA array technology and establish the degree of correlation between any compound-induced effects on gene expression with those at the level of histological examination.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Paul Scott-Stevens

PROVIDER: E-MEXP-52 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

An evaluation of a low-density DNA microarray using cytochrome P450 inducers.

Meneses-Lorente Georgina G de Longueville Françoise F Dos Santos-Mendes Sofia S Bonnert Timothy P TP Jack Andrew A Evrard Stéphanie S Bertholet Vincent V Pike Andrew A Scott-Stevens Paul P Remacle José J Sohal Bindi B

Chemical research in toxicology 20030901 9

The aim of this study was to validate a low-density DNA microarray "Rat HepatoChip", which contains 59 genes from a range of potential toxic markers and drug metabolism-related genes. Liver mRNA was isolated from rats dosed with six different chemicals, dexamethasone, troleandomycin, miconazole, clotrimazole, and methylclofanapate, which are all known to induce different cytochrome P450 genes, and isoniazid, which does not cause histopathological changes. Replicate microarrays were used to measu ...[more]

PMID: 12971794

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Project description:The number of legacy chemicals without toxicity reference values combined with the rate of new chemical development are overwhelming the capacity of the traditional risk assessment paradigm. More efficient approaches are needed to quantitatively estimate chemical risks. In this study, rats were dosed orally with multiple doses of six chemicals for 5 days, 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points-of-departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with 8 additional chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two suggesting that for the current chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a practical framework for application of transcriptomic data to chemical risk assessment. Four to five week-old rats were exposed in dose-response and for multiple durations to 6 chemicals. The chemicals were 1,2,4-tribromobenzene (CAS No. 615-54-3), 2,3,4,6-tetrachlorophenol (CAS No. 58-90-2), bromobenzene (CAS No. 108-86-1), 4,4'-methylenebis(N,N-dimethyl)benzenamine (CAS No. 101-61-1), hydrazobenzene (CAS No. 122-66-7), N-nitrosodiphenylamine (CAS No. 86-30-6). For 1,2,4-tribromobenzene and 2,3,4,6-tetrachlorophenol, male Sprague Dawley (Rat/Crl:CD(SD)) rats were used. For bromobenzene and hydroazobenzene, male F344/DuCrl rats were used. For 4,4'-methylenebis(N,N-dimethyl)benzenamine and N-nitrosodiphenylamine, female F344/DuCrl rats were used. The exposure durations were 5 days, 2 weeks, 4 weeks, and 13 weeks. The dose and route of exposure are provided with the individual sample annotations. With each chemical treatment, a matched vehicle control group was run concurrently with the exposure. Gavage exposures were administered 7 days per week and feed exposures were provided 7 days per week. At the appropriate time point, animals were euthanized with a lethal intraperitoneal injection of sodium pentobarbital. For the liver, slices from each of the lobes were mixed together and used for microarray analysis. For the thyroid, the gland was transversely sectioned and the bottom portion was used for microarray analysis. For the bladder, the organ was longitudinally bisected, a slice was removed for histology and the remainder of the organ was minced and used for microarray analysis. Microarrays were run on five rats per dose per time point.

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Dataset Information

Transcription profiling of rat liver response to CYP450 inducers for array validation

Publications

An evaluation of a low-density DNA microarray using cytochrome P450 inducers.

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